1. Field of the Invention
The invention relates to novel phosphocholine derivatives which are inhibitors of the enzyme phospholipase A.sub.2.
2. Description of the Prior Art
The enzyme phospholipase A.sub.2 (phosphalide 2-acylhydrolase, PCA.sub.2) is generally accepted as being the key enzyme responsible for exerting rate-determining regulatory control over the release of polyunsaturated fatty acids from phospholipids [Flower, R. Q., et al., Biochem. Pharmac., 25, 285 (1976); Lapetina, E. G., et al., Annu. Rep. Med. Chem., 19, 213 (1984)]. This enzyme has been isolated from many sources and is known to cleave snglycerophospholipids at the 2-position thus giving rise ultimately to the biosynthesis of platelet activating factor, prostaglandins, leukotrienes and prostacyclin [Dennis, E. A., The Enzymes; Academic Press: New York; Vol. 16, Chapter 9 (1983)]. The roles of these mediators in the inflammatory response associated with various diseases and physiological states is well known. Included among these diseases are asthma, arthritis, pancreatitis, myocardial ischemia, inflammation, pain, edema and their inflammatory related disorders.
Various compounds which are known to be inhibitors of phospholipase A.sub.2 have been described in U.S. Pat. No. 4,959,357, 4,933,365 and in Wilkenson, Anti Inflammatory Phospholipase A.sub.2 Inhibitors, Drugs of The Future, Vol. 15, No. 2, p 139-148 (1990). Various phosphocholine derivative compounds having anti hypertension activity have been disclosed in U.S. Pat. Nos. 4,640,913, 4,697,031, 4,699,990, 4,703,130, 4,939,127, 4,762,942, 4,883,816 and 4,894,367.